Perspectives on the Evolution of Therapy for Atrial Fibrillation

Atrial fibrillation: the problem

Atrial fibrillation (AF) remains the leading arrhythmia in North America, both in numbers of patients affected and the frequency of accompanying sequelae. The prevalence continues to increase, despite progress in the treatment of contributing factors.

Although 1% of individuals in their 60s may have AF, the prevalence increases to 10% to 12% in individuals older than 80 years. Currently 2.5 million Americans have AF, but with the aging population and improved cardiovascular survival, this number may increase to 5 million to 6 million by the year 2050.

Atrial fibrillation is an increasing burden on the global health care system because of the numbers of patients affected, the impact of stroke, and the cost of both inpatient and outpatient therapy.

In most patients, AF is initially paroxysmal. Other patients, particularly those with underlying heart disease, may have more persistent or even chronic AF. Nevertheless, the previously held belief that most paroxysmal AF ultimately progresses to a chronic form has been questioned. Recent studies have suggested that progression occurs in only 20% to 40% of patients over the course of 3 to 5 years, although longer-term data are lacking.

Drug therapy for AF

Because of stroke risk, most patients require some form of antithrombotic therapy in the form of aspirin or warfarin. Those patients with no risk factors may completely forgo antithrombotic therapy, while the recent ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation have suggested that therapy with aspirin alone is adequate in those at low risk with a CHADS score less than 1.

Patients with several risk factors are at higher risk, necessitating anticoagulation therapy with warfarin. This recommendation is based on an extensive series of large mortality studies consistently demonstrating the benefit of antithrombotic therapy. Risk factors include:

• Age >75 years
• Hypertension
• Diabetes
• Prior stroke or transient ischemic attack
• Left ventricular dysfunction

Despite clear guidelines and extensive experience with thromboembolic events, many patients who would benefit from antithrombotic therapy do not receive it.

Many patients have a rapid ventricular response rate during AF, which is responsible for symptoms. In some cases, rapid rates may also result in tachycardia-induced cardiomyopathy. While this condition occurs relatively uncommonly in the absence of other heart disease, the possibility of an AF contribution to ventricular dysfunction should be considered in patients who have a rapid ventricular response rate and reduced ejection fraction.

Establishing appropriate rate control, however, requires some assessment of rate during rest and exertion. Most guidelines and recent clinical trials recommend that resting rates during AF be less than 90 to 100 bpm, with exercise heart rates maintained at less than 110 to 120 bpm.

Restoration of normal sinus rhythm may be the most effective means of rate control. A number of studies over the past 30 years have shown the usefulness of membrane-active, anti-arrhythmic drug therapy for maintaining sinus rhythm.

Approximately 30% to 40% of patients treated with antiarrhythmic therapy achieve control over the course of 1 year of follow-up. These data have been validated by larger comparative clinical trials such as the AFFIRM trial. Similar results have been reported in RACE, STAF, and other studies designed to compare rate and rhythm control therapy.

Although an increase in mortality may accompany AF, comparative studies examining the utility of rate vs rhythm control therapy have had disappointing results. The AFFIRM trial, for example, showed no difference in overall mortality over the course of long-term follow-up with either treatment strategy. Similarly, the RACE, PIAF, and STAF studies yielded similar findings.

Additionally, the AF-CHF trial, which involved 1,376 patients with AF, also failed to demonstrate any difference in the end points of total mortality, worsening heart failure, or the composite of cardiovascular mortality, stroke, or worsening heart failure.

Furthermore, bradycardia and rehospitalization were more common in those treated with anti-arrhythmic drugs intended to maintain sinus rhythm. These findings may have been attributable to the following scenarios:

1. Other factors, including underlying disease, were responsible for the morbidity and mortality in AF patients, such that AF was a risk marker for mortality, rather than a risk factor.
2. A benefit from treatment with antiarrhythmic drug therapy may have been masked by the occurrence of organotoxicity or proarrhythmic events.
3. Silent AF in patients treated with rhythm control or undetected sinus rhythm in those treated with rate control drugs may have decreased the ability of the AF-CHF trial protocol to detect real differences in overall outcomes.

Despite the pessimism generated by these studies, the results of the recent ATHENA trial have encouraged reconsideration of drug therapy for AF. In comparing the class III anti-arrhythmic agent dronedarone with placebo in more than 4,500 patients, this study showed:

• 24% reduction in cardiovascular hospitalization or mortality
• 29% decrease in cardiovascular mortality
• 26% decrease in cardiovascular hospitalization with active therapy at 22 ± 5 months of follow-up

There were significantly lower rates of acute ischemic syndrome and stroke with dronedarone therapy when rates of proarrhythmia and heart failure were also low. These data support the potential for cancellation of benefit from drug therapy by untoward toxicities of drug interventions, although the control rate with this drug is less than that of amiodarone.

Map of atrial activation

Enlarge

Nonpharmacologic therapy for AF

Atrial fibrillation ablation has been shown in a number of observational studies to be of benefit in eliminating AF, reducing its frequency and improving patients' quality of life. In most studies, 75% to 85% of patients with paroxysmal AF have been rendered free of this arrhythmia over the course of 1 year of observation.

In patients with persistent or chronic AF and those with underlying disease, AF is decreased in 10% to 20% of patients. After longer-term follow-up, the ablation of patients with more advanced underlying disease, and a more critical view of treatment benefit without additional anti-arrhythmic drugs or repeat ablative intervention, these overall success rates are lower than the more optimistic values touted in the first part of this decade.

Douglas L. Packer, M.D., director of the Section of Electrophysiology at Mayo Clinic and the 2010-2011 president of the Heart Rhythm Society, reviewed outcomes of ablation at Mayo Clinic. He found that over 2 years of long-term follow-up:

• Response to ablation was excellent in more than 75% of patients with paroxysmal AF.
• Patients with persistent and chronic AF likewise have shown enhanced benefit, although a more aggressive ablative approach has been required.
• In patients with paroxysmal AF, ablation for the isolation of pulmonary veins may be sufficient, while wider-area circumferential ablation with additional linear ablation or energy delivery directed at the underlying substrate has been required.

Additional review demonstrated notable benefit in patients with underlying dilated cardiomyopathies. In many patients, not only was AF eliminated, but a substantial improvement in ejection fraction was observed, particularly in those with nonischemic left ventricular dysfunction.

Several recent studies have gone beyond observational reports to compare the efficacy of ablative vs drug therapy in patients with paroxysmal AF. The CACAF, RAAFT, APAF, and A4 trials demonstrated a 76% recurrence rate in patients treated with drug therapy vs 24% recurrence in those treated with ablative intervention. These studies were limited, however, because of shorter-term follow-up and the exclusion of patients with underlying disease or advancing age. The impact of ablative therapy on the overall cost of health care is less certain.

Indications for ablative intervention

Even in the absence of cost data, there is sufficient information from observational studies, meta-analyses, and comparative studies to support more widespread application of AF ablation in patients failing a single antiarrhythmic drug because of AF recurrence or intolerability.

The Guidelines for the Management of Patients With Atrial Fibrillation, endorsed by the American Heart Association (AHA) and the American College of Cardiology (ACC), recommend this nonpharmacologic approach as second-line therapy. The Expert Consensus Statement on Catheter and Surgical Ablation for Atrial Fibrillation: Recommendations for Personnel, Policy, Procedures and Follow-up, developed by the Heart Rhythm Society and endorsed by the AHA and ACC, comes to a similar conclusion. A number of centers are moving toward a primary therapy role for ablation, as success rates increase and complication rates decline.

In clinical practice, it is crucial to be clear on the indication for any intervention in AF patients. Of primary importance is the need to prevent stoke or other peripheral thromboembolic events. Warfarin therapy has been best demonstrated to reduce this risk.

Additional studies will be required to establish a benefit in this area with membrane-active drug therapy or ablation. The role of therapy to establish and maintain sinus rhythm in patients with left ventricular dysfunction is acceptably clear-cut in recent ablation studies. Of greatest importance is the need to reduce or eliminate AF in symptomatic patients, which remains the primary indication for ablative intervention.

Patients who have failed to respond to 1 drug may be good candidates for intervention, although the anticipated success rate depends on the type of AF and the presence of underlying left ventricular or left atrial dysfunction. Age appears to be a less important issue than previously thought. Patients with underlying valvular heart disease and hypertrophic cardiomyopathy have excellent short-term outcomes although much more aggressive procedures are required.

Experience with pulmonary vein isolation at Mayo Clinic

Since 1997, more than 2,500 pulmonary vein isolation procedures for the treatment of AF have been performed at Mayo Clinic. In the most recent review:

• Seventy-three% of patients with paroxysmal AF and 66% of patients with persistent AF maintained sinus rhythm for 1 year after the procedure without anti-arrhythmic drug therapy.
• Another 10% of patients with paroxysmal AF and 11% with persistent AF were able to maintain sinus rhythm with previously ineffective anti-arrhythmic drug therapy.
• The procedure was repeated in 13% of patients.
• Complication rates have been low, with severe pulmonary vein stenosis occurring in 0.8% and cardiac tamponade occurring in 2.1%.
• There have been 2 atrioesophageal fistulas.
• The majority of patients (71%) were younger than 65 years.

Ongoing large multicenter trials

While observational studies and limited randomized comparisons demonstrate symptomatic improvement in patients undergoing ablation and early data suggest a cost benefit, larger long-term studies are required to establish a mortality benefit and a reduction in stroke risk. As a result, the CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy in Atrial Fibrillation) trial was designed.

This study, originating from Mayo Clinic, will examine the benefit of ablation vs drug therapy in 3,000 patients with AF enrolled in 140 centers around the world. Mayo Clinic recently received $48 million in grants from the National Institutes of Health and from industry to lead this collaborative effort.

The study will also establish long-term complications of AF treatment and their prevention by appropriate ablative or drug therapy, and determine the actual impact of the arrhythmia and its treatment on a patient's quality of life and health care costs.

Until these studies are completed, the application of ablative intervention will continue to be guided by a decade of observational studies and smaller randomized clinical trials, as well as information coming from national and international ablation registries.

Clinical trials

Clarification of optimal anticoagulation through genetics (COAG) trial

A randomized, multicenter, double-blind clinical trial to evaluate the efficacy of clinical plus genetic information to guide the initiation of warfarin therapy and to improve anticoagulation control for patients. The protocol includes:

• Warfarin therapy for at least 3 months
• Target INR 2-3
• Study enrollment before receiving the first dose
• Follow-up visits at the Gonda 4 Thrombophilia Clinic

For more information, contact Nancy Lexvold, R.N., at
507-255-7013 or Robert D. McBane, M.D., at
507-266-3964.

Anatomy vs physiology-guided ablation for atrial fibrillation

A study to establish the differential success rate for complete elimination of atrial fibrillation (AF) with combined wide-area circumferential ablation and linear ablation vs combined wide-area circumferential ablation and complex fractionated atrial electrogram (CFAE) ablation. Inclusion criteria are:

• History of symptomatic persistent/permanent AF
• Patient recommended for catheter-based, wide-area pulmonary vein isolation
• Available for 13 months of follow-up after ablation.

For more information, contact Nancy Lexvold, R.N., at
507-255-2501 or Yong-Mei Cha, M.D., at
507-255-2501.